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Original Study

Assessing the Burden of Infant Deaths Due to Herpes Simplex Virus, Human Immunodeficiency Virus, and Congenital Syphilis: United States, 1995 to 2017

Slutsker, Jennifer Sanderson MPH; Schillinger, Julia A. MD, MSc∗,†

Author Information
Sexually Transmitted Diseases: August 2021 - Volume 48 - Issue 8S - p S4-S10
doi: 10.1097/OLQ.0000000000001458
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Infection with herpes simplex virus (HSV) in the newborn period (neonatal herpes) can cause serious, life-threatening illness and long-term neurologic sequelae.1 The severity of infection is based on the extent of disease, ranging from infections limited to the skin, eyes, and/or mucous membranes to central nervous system infection or disseminated infection involving multiple-organ systems. Infants surviving central nervous system infection have high rates of neurologic sequelae, and those with disseminated disease have high rates of mortality (29%) despite the availability of effective antiviral therapy.2

Herpes infection can be acquired congenitally; however, in the majority of cases (~85%), transmission results from exposure to HSV shed from the birthing parents’ genital tract during labor and delivery. The risk of herpes infection is highest among infants born to pregnant people who newly acquire HSV during the third trimester.2 Most pregnant people who deliver an infant with neonatal herpes show no evidence of infection at delivery and report no history of herpes infection.1 Most infections present in the first 2 to 3 weeks of life, reflecting perinatal transmission. However, infection can also be transmitted postnatally, usually from an infected caretaker, as has been described during the ritual Jewish circumcision practice of direct orogenital suction.3

There have been significant advances in the detection and treatment of neonatal herpes infection, such as the application of polymerase chain reaction (PCR) tests to cerebrospinal fluid and blood specimens4 and the use of intravenous high-dose acyclovir.5 However, the national burden of neonatal herpes infection has not been well characterized because the condition is not nationally notifiable, and few states and local jurisdictions conduct routine surveillance.6 Estimates of neonatal herpes incidence in the United States vary (1.0–76.2 per 100,000 live births)6,7 due to some combination of real differences in the prevalence of genital herpes infection in adults of child-bearing age by region and population subgroups, and as an artifact of methodological differences in measurement (e.g., study design, study population, and data sources). Long-term trends may be further impacted by broader availability of PCR testing across time.

We are aware of only 3 US studies that characterize herpes-related infant mortality in a defined population.8–10 All 3 investigations were conducted at the jurisdiction level and searched death certificates for disease codes indicating HSV as a cause of death for infants. Despite different observation periods and geographies, all studies calculated similar HSV-related death rates: California (0.64–0.83/100,000 live births from 1995 to 2003),8 New York City (0.82/100,000 from 1981 to 2013),9 and Florida (0.6–2.0/100,000 from 2011 to 2017).10 The lack of recent and national data assessing neonatal herpes mortality remains a substantial knowledge gap that this investigation aims to address.

Our primary objective is to characterize trends in HSV-related infant deaths across a wide time frame in the United States, an effort that may also provide insights into disease burden trends given the absence of national incidence data. Secondarily, we aim to compare trends in HSV-related infant deaths with trends in deaths from congenital syphilis (CS) and human immunodeficiency virus (HIV), 2 other perinatal infections that are nationally notifiable. Most CS infections occur in utero via transplacental transmission, and a majority of CS-related deaths are classified as syphilitic stillbirths.11 Although CS can be prevented with timely treatment during pregnancy, both CS cases and deaths have increased steadily in the United States since 2012.12 In contrast, most HIV transmission occurs during the intrapartum period,13 and the incidence of perinatal HIV and deaths among children (<13 years of age at death) living with HIV are now rare events in the United States.14 Despite the clinical and epidemiologic differences between CS and HIV, these perinatal infections are both monitored through robust, long-standing surveillance systems and remain urgent priorities for public health prevention,15,16 and therefore help to contextualize trends in HSV-related infant deaths, which are neither reportable nor the focus of public health prevention efforts.

MATERIALS AND METHODS

Data Source

To calculate the number of infant deaths related to HSV, CS, and HIV, we obtained public use data files from the National Center for Health Statistics (NCHS) Online Data Portal.17 Annual period linked birth-infant death files were downloaded for each year between 1995 and 2017. These files contain records of all infant deaths in the United States that occurred in a specific year after linking the death certificate to the corresponding birth certificate. These files include infants who were born alive and died in the first 365 days of life and exclude stillbirths. Only data files for infant deaths in the United States or District of Columbia were assessed in the analysis (i.e., US territories data were not examined).

Study Population

The population of interest included all infants who died in the United States from 1995 to 2017 and whose death certificate had an International Classification of Diseases (ICD) code for HSV, HIV, or CS listed. Cause of death information is captured through more than one approach in the period linked files: the “record axis” variables were selected for this analysis because they “best describe the overall medical certification portion of the death certificate” and are “comparable to underlying cause of death classification.”18 All record axis fields were queried to identify any infant death with an ICD code indicating HSV, HIV, or CS as a cause of death (Table 1). Two revisions of the ICD system were used during the study period, and as such, ICD codes of interest differed based on the infant's year of death.

TABLE 1 - Criteria Used to Identify Infant Deaths Related to Herpes Simplex Virus (HSV), Human Immunodeficiency Virus (HIV), and Congenital Syphilis (CS), by Infant Age at Death, Year of Death, and International Classification of Diseases (ICD) Revision*
Disease Infant Age at Death, d ICD-9 System
(Death Certificates: 1995–1998)
ICD-10 System
(Death Certificates: 1999–2017)
HSV 0–42 054 (herpes simplex) P35.2 (congenital herpes viral infection)
B00 (herpes viral infection)
A60 (anogenital herpes viral infection)
43–365 054 (herpes simplex) and 771.2/779.8 (other infection or condition originating in the perinatal period) P35.2 (congenital herpes viral infection)
B00 (herpes viral infection) and P002 (newborn infected by maternal infectious or parasitic disease)
A60 (anogenital herpes viral infection) and P002 (newborn infected by maternal infectious or parasitic disease)
CS 0–365 d 090 (congenital syphilis) A50 (congenital syphilis)
091 (early syphilis, symptomatic) A51 (early syphilis)
092 (early syphilis, latent) A52 (late syphilis)
093 (cardiovascular syphilis) A53 (other and unspecified syphilis)
094 (neurosyphilis)
095 (other forms of late syphilis, with symptoms)
096 (late syphilis, latent) 097 (other and unspecified syphilis)
HIV 0–365 042 (HIV with specified conditions) B20 (HIV resulting in infectious and parasitic diseases)
043 (HIV causing other specified
conditions)
B21 (HIV resulting in malignant neoplasms)
044 (other HIV infections) B22 (HIV resulting in other specified diseases)
B23 (HIV resulting in other conditions)
B24 (unspecified HIV, includes AIDS not otherwise specified, AIDS-related complex not otherwise specified)
*Criteria based on Sampath et al.9

Using the criteria from prior investigations, infant deaths were then categorized to indicate whether the death was related to HSV, HIV, or CS (Table 1).8,9 For HSV-related deaths, classification depended on the infant's age at the time of death. Infants who died at 43 days or older were required to have an ICD code indicating that the infection originated in the perinatal period (771.2 or 779.8 under the ICD-9 system; P35.2 or P00.2 under the ICD-10 system). This conservative approach increases the likelihood that infant deaths were related to neonatal herpes and not to an infection acquired after the neonatal period. All infant deaths with an ICD code for HIV or CS were classified as being related to the identified infection, regardless of infant age at death or the presence of a code specifically indicating perinatal infection. This method assumed that infants who died within 1 year of life with HIV or syphilis as a cause of death had acquired this infection congenitally or perinatally.9

Variables of Interest

For all identified infant deaths, basic demographic characteristics were abstracted from the period linked files including infant sex, age group of the birthing parent, and race and Hispanic/Latino origin of the birthing parent. We use the term birthing parent instead of mother in recognition that all people who deliver an infant may not identify as women or mothers. Characteristics of birthing parents reflect information listed on the birth certificate, a strength of this data source, particularly for race/ethnicity, as the parent is more likely to report information directly on the birth certificate, whereas information may be collected indirectly and less reliability on the death certificate (e.g., recorded by funeral directors based on observation).19

The collection and aggregation of information on race/ethnicity varied across the study period. The 2003 Revision of the US Standard Certificate of Live Birth enabled parents to report multiple races; however, implementation of this revised certificate occurred in phases.20 All states did not report using the multiple-race format until the 2017 period linked file, limiting the ability to examine race/ethnicity with the granularity of the Office of Management and Budget standards.18 To describe race/ethnicity of the birthing parent, we used an NCHS variable (“mother's race/Hispanic origin”), which, until 2017, involved “bridging” responses to race and Hispanic origin questions into one group. Categories varied across study years but could be consistently collapsed into the following: Hispanic/Latino (Mexican, Puerto Rican, Cuban, Central and South American, other Hispanic), White, Black, other races, and origin unknown or not stated.18 The Hispanic/Latino category includes people of any race, and all other categories exclude those who identified as Hispanic/Latino.

Analysis

The primary objective was to calculate the number of infant deaths related to HSV, CS, and HIV. After identifying all infants who met the inclusion criteria (Table 1), we calculated the frequency of infant deaths by year of death, infant sex, age of the birthing parent, and race/ethnicity of the birthing parent. A small proportion of infant death records cannot be matched to the corresponding birth certificate each year (e.g., 0.4% in 2017); to account for these “unlinked” records, the NCHS generates a weight for each infant death based on state of residence and infant age at death.18 In alignment with NCHS standards, we applied these weights to all frequency calculations and excluded deaths among infants who were born to a nonresident of the 50 US states or District of Columbia.18

To enable calculation of case rates, we obtained the number of live births in the United States, both overall and by characteristics of interest, for each year, from annual National Vital Statistics Reports that include infant mortality statistics from the period linked birth/infant death data sets.21 These reports were not available for 2011 to 2012 and 2014 to 2016, in which cases, the numbers of live births were identified and extracted from the “User Guides” for the period linked files from the NCHS Online Data Portal.17 Consistent with NCHS guidance, we estimated 95% confidence intervals (CIs) for rate calculations following a Poisson probability distribution when the number of events in the numerator was less than 100.18 Nonoverlapping 95% CIs were considered to be significantly different at the 95% level.

This investigation was not subject to review by the institutional review boards of the Centers for Disease Control and Prevention or New York City Department of Health and Mental Hygiene, as it used publicly available data that were collected for routine surveillance activities. The authors abided by the NCHS Data User Agreement, using data only for statistical reporting and analysis, and making no attempts to identify or link observations to any individual person or establishment.22

RESULTS

Among the 609,758 infant deaths that occurred in the United States from 1995 to 2017, we identified 1591 infant deaths related to the perinatal infections of interest: 1271 related to HSV (79.9%), 234 to HIV (14.7%), and 86 to CS (5.4%; Table 2). No infant had an ICD code for >1 of these infections listed on the death certificate. The overall rate of HSV-related deaths (1.37/100,000 live births; 95% CI, 1.30–1.45) was significantly higher than the rates for HIV-related (0.25/100,000; 95% CI, 0.22–0.29) and CS-related (0.09/100,000; 95% CI, 0.07–0.11) deaths (Table 3). When assessing trends across time, the annual rate of HSV-related deaths per 100,000 was significantly greater than the rates of HIV- and CS-related deaths in each year from 1999 to 2017 (Fig. 1).

TABLE 2 - Number of Infant Deaths During the First Year of Life, With Herpes Simplex Virus (HSV), Human Immunodeficiency Virus (HIV), and Congenital Syphilis (CS) Listed on the Death Certificate, United States, 1995 to 2017
Year of Death No. HSV-Related Deaths No. HIV-Related Deaths No. CS-Related Deaths
1995 33 64 10
1996 23 44 9
1997 35 20 5
1998 37 20 4
1999 41 12 3
2000 53 12 2
2001 37 12 1
2002 51 9 3
2003 54 5 4
2004 51 4 1
2005 52 4 0
2006 49 9 1
2007 68 5 6
2008 69 1 1
2009 60 3 1
2010 56 0 3
2011 82 3 4
2012 69 2 1
2013 63 1 5
2014 67 1 4
2015 74 2 3
2016 75 0 5
2017 68 0 8

TABLE 3 - Number of Infant Deaths Related to Herpes Simplex Virus (HSV), Human Immunodeficiency Virus (HIV), and Congenital Syphilis (CS), by Infant and Birthing Parent Characteristics, United States, 1995 to 2017
HSV HIV CS
n (%) Rate Per 100,000 Live Births (95% CI) n (%) Rate Per 100,000 Live Births (95% CI) n (%) Rate Per 100,000 Live Births (95% CI)
Overall 1271 (100.0) 1.37 (1.30–1.45) 234 (100.0) 0.25 (0.22–0.29) 86 (100.0) 0.09 (0.07–0.11)
By infant sex
 Female 606 (47.6) 1.28 (1.18–1.38) 102 (43.7) 0.22 (0.17–0.26) 41 (47.7) 0.09 (0.06–0.12)
 Male 666 (52.4) 1.47 (1.36–1.58) 132 (56.4) 0.29 (0.24–0.34) 45 (52.3) 0.10 (0.07–0.13)
By age of birthing parent
 <20 y 377 (29.7) 4.17 (3.75–4.59) 23 (9.9) 0.26 (0.16–0.39) 16 (19.2) 0.18 (0.10–0.30)
 20–24 y 522 (41.0) 2.35 (2.15–2.55) 70 (29.8) 0.32 (0.25–0.40) 25 (28.7) 0.11 (0.07–0.16)
 25–29 y 219 (17.2) 0.85 (0.74–0.96) 60 (25.7) 0.23 (0.18–0.30) 19 (22.6) 0.07 (0.04–0.12)
 30–34 y 104 (8.2) 0.46 (0.37–0.55) 54 (23.0) 0.24 (0.18–0.31) 18 (21.3) 0.08 (0.05–0.13)
 35–39 y 41 (3.2) 0.38 (0.27–0.52) 23 (9.9) 0.21 (0.14–0.32) 6 (7.0) 0.06 (0.02–0.12)
 ≥40 y 9 (0.7) 0.37 (0.17–0.71) 4 (1.7) 0.17 (0.05–0.43) 1 (1.2) 0.04 (0.00–0.23)
By race and Hispanic/Latino origin of birthing parent
 White, non-Hispanic/Latino 694 (54.6) 1.34 (1.24–1.44) 56 (23.9) 0.11 (0.08–0.14) 10 (12.1) 0.02 (0.01–0.04)
 Black, non-Hispanic/Latino 388 (30.5) 2.86 (2.58–3.15) 136 (58.3) 1.01 (0.84–1.18) 49 (57.0) 0.36 (0.27–0.48)
 Hispanic/Latino 138 (10.9) 0.68 (0.56–0.79) 36 (15.3) 0.17 (0.12–0.24) 22 (26.2) 0.11 (0.07–0.17)
 Other races, non-Hispanic/Latino 40 (3.2) 5 (2.2) 1 (1.2)
 Unknown or not stated 11 (0.9) 1 (0.4) 3 (3.6)

Figure 1
Figure 1:
Rate of infant deaths related to herpes simplex virus (HSV), human immunodeficiency virus (HIV), and congenital syphilis (CS) per 100,000 live births, with 95% confidence intervals, United States, 1995 to 2017.1Brackets represent 95% confidence intervals for rate calculations.2Denominators for rate calculations included the number of live births in the United States, which were obtained from annual National Vital Statistics Reports (https://www.cdc.gov/nchs/nvss/linked-birth.htm) and User's Guides (https://www.cdc.gov/nchs/data_access/vitalstatsonline.htm).

Herpes Simplex Virus

The number of HSV-related infant deaths increased from 33 deaths in 1995 to 68 deaths in 2017 (Table 2), with a median of 54 deaths per year. The death rate increased in parallel (Fig. 1), with a significant rise from 0.60 deaths per 100,000 live births in 1996 (95% CI, 0.38–0.90) to a peak of 2.07 deaths per 100,000 in 2011 (95% CI, 1.64–2.56). From 2007 to 2017, HSV-related mortality rates remained significantly elevated over the minimum rate observed in 1996.

Across the study period, a similar number and rate of HSV-related deaths occurred in infants assigned female (606/1271; 47.6%) and male (666/1271; 52.4%) sex at birth (Table 3). An inverse relationship was observed between age of the birthing parent and rate of HSV-related deaths; the rate decreased significantly from 4.17 deaths per 100,000 among parents younger than 20 years (95% CI, 3.75–4.59) to 0.37 among parents 40 years or older (95% CI, 0.17–0.71). Although the highest proportion of birthing parents linked to an HSV-related death was White (694/1271; 54.6%), the mortality rate was significantly elevated among Black parents (2.86/100,000; 95% CI, 2.58–3.15) when compared with White (1.34/100,000; 95% CI, 1.24–1.44) and Hispanic/Latino (0.68/100,000; 95% CI, 0.56–0.79) parents. Most HSV-related infant deaths occurred during the first 15 days of life (Fig. 2), with a mean age at death of 15.6 days (interquartile range, 8–16 days).

Figure 2
Figure 2:
Age at death among infants with herpes simplex virus (HSV) listed on the death certificate (n = 1271), United States, 1995 to 2017.

Human Immunodeficiency Virus

Infant deaths related to HIV declined substantially from 64 deaths in 1995 to 0 deaths in 2016 to 2017, with a median of 4 HIV-related deaths per year (Table 2; Fig. 1). Although the rate of HIV-related deaths (1.64/100,000 live births; 95% CI, 1.27–2.10) significantly exceeded the rates of both HSV-related (0.83/100,000; 95% CI, 0.57–1.17) and CS-related deaths (0.26/100,000; 95% CI, 0.13–0.48) in 1995, the number and rate of HIV-related deaths was the lowest of these 3 infections in the last 5 years of the study period (2013–2017).

When assessing HIV-related deaths by infant and birthing parent characteristics, there were no significant differences in mortality rates by infant sex or age of the birthing parent (Table 3). Most HIV-related deaths were among infants born to Black birthing parents (136/234; 58.3%); the rate (1.01/100,000; 95% CI, 0.84–1.18) was higher than the rate among infants born to Hispanic/Latino (0.17/100,000; 95% CI, 0.12–0.24) and White (0.11/100,000; 95% CI, 0.08–0.14) parents. Among infants with an HIV-related death, the mean age at death was 166.7 days (interquartile range, 89–248 days).

Congenital Syphilis

The number of CS-related infant deaths declined from 10 deaths in 1995 to minimal counts in the early 2000s (between 0 and 4 deaths/year from 2000 to 2006), subsequently increasing in the mid-2010s to a peak of 8 deaths in 2017 (Table 2). The median number of CS-related infant deaths each year (n = 3) was also the lowest among the infections examined. There were no significant changes in the rate of CS-related deaths per 100,000 live births across the study period (Fig. 1).

The number and rate of CS-related deaths were similar among infants assigned male and female sex at birth (Table 3). The rates of CS-related deaths were slightly elevated among infants born to a parent younger than 20 years (0.18/100,000; 95% CI, 0.10–0.30) or 20 to 24 years old (0.11/100,000; 95% CI, 0.07–0.16); however, no clear trend was observed across age groups. The majority of CS-related deaths occurred among infants born to Black (49/86; 57.0%) and Hispanic/Latino (22/86; 26.2%) parents; differences in mortality rates by race/ethnicity were statistically significant: Black (0.36/100,000; 95% CI, 0.27–0.48), Hispanic/Latino (0.11/100,000; 95% CI, 0.07–0.17), and White (0.02/100,000; 95% CI, 0.01–0.04). Measures of central tendency for age at CS-related death differed substantially, with a mode of 0 days, median of 4 days, and mean of 34.1 days.

DISCUSSION

When examining infants who were born alive and died within 1 year in the United States from 1995 to 2017, the number of HSV-related infant deaths exceeded those related to CS and HIV, 2 other perinatal infections that have received specific public health attention and categorical funding.15,16 Over the same period, the infant death rate related to HSV more than doubled. A clear inverse relationship was observed between birthing parent age and HSV-related death rates, such that the death rate was significantly higher among infants born to younger birthing parents when compared with older birthing parents. For each of the 3 infections, rates of deaths were highest among infants born to Black birthing parents.

There are several hypothesized explanations for the rising number of HSV-related infant deaths; however, it remains challenging to understand trends without national surveillance for laboratory-confirmed infections, and the more detailed information such surveillance would yield. Increases in HSV-related infant deaths may be due to improved ascertainment resulting from the development and broader availability of PCR diagnostics across the wide study period.4 The rise in infant deaths may also be associated with the decreasing seroprevalence of HSV type 1 (HSV-1) among adolescents in the United States; more young people are susceptible to HSV-1 infection and at risk for acquiring primary genital HSV-1 infection during pregnancy.23,24 This hypothesis is consistent with the inverse relationship we observed between HSV-related deaths and age of the birthing parent. Although it was not possible to examine in this descriptive analysis of vital records, further exploration of the association between birthing parent age, parity, and HSV serotype may help elucidate reasons for trends in HSV-related infant deaths. Additional analyses examining whether increases in HSV-related deaths are consistent across birthing parent age and race/ethnicity may also inform understanding of the observed trends.

Prior investigators have identified associations between younger birthing parent age and having an infant with neonatal herpes, and suggested that HSV serologic screening targeted to pregnant people younger than 25 years (or those who have a partner younger than 20 years or with unknown age) could prevent a large proportion of neonatal herpes cases in a cost-effective manner.25 Our analysis adds new evidence that herpes-infected infants born to younger women (<25 years of age) are at disproportionate risk for death, a finding that warrants further investigation.

Although patterns in HIV- and CS-related deaths differ from those observed for HSV-related deaths, the findings remain consistent with national trends. Deaths related to HIV peaked in 1995 and steadily decreased thereafter, reaching a nadir of 0 deaths in both 2016 and 2017. This corresponds with a >95% decline in perinatal HIV infections in the United States since the early 1990s, related to advancements in HIV prevention and treatment, and focused efforts aimed at eliminating parent-to-child HIV transmission.16 For CS, reductions in infant deaths were observed throughout the 1990s and early 2000s, followed by increases in 2016 and 2017. This “U-shaped” curve also mirrors US surveillance data on CS incidence, showing stable, low rates of CS and its adverse sequelae for several years before a resurgence in 2012.12 It is important to note that the period linked files only include infants who were born alive and died during the first year of life and therefore do not capture stillbirths. Because most deaths related to CS are classified as syphilitic stillbirths, this analysis does not fully capture all mortality related to this infection.11 For example, in 2017, 64 syphilitic stillbirths were reported in national surveillance data, suggesting that the number of CS-related deaths might approximate or outnumber the number of HSV-related deaths should syphilitic stillbirths be included.26 However, the consistency of our HIV and CS findings with national trends supports the utilization of vital statistics records for characterizing infant deaths related to these infections over time.

The national trends observed in HSV-related infant mortality align with the findings from past investigations of neonatal herpes deaths in specific geographies. In New York City from 1981 to 2013, the authors identified 0.82 HSV-related deaths per 100,000 live births (95% CI, 0.57–1.15), with the mortality rate increasing in the final decade of the study period (2004–2013).9 In a similar investigation that identified HSV-related deaths using ICD codes on death certificates in California from 1995 to 2003, the rate of HSV-related deaths ranged from 0.64 to 0.83 deaths per 100,000 based on the ICD system.8 Finally, using multiple data sources (infant death records, provider reporting, electronic laboratory reporting), investigators in Florida found HSV-related death rates ranging from 0.6 to 2.0 per 100,000, with the highest estimate based on infant deaths identified through vital statistics records.10 Our national estimate of 1.37 HSV-related deaths per 100,000 falls within or near to these estimates produced at the local level; furthermore, our findings reflect the pattern of increasing rates over time identified in New York.

Across all 3 infections, infants born to Black birthing parents had the highest mortality rates, and for HIV and CS, these infants accounted for nearly 60% of all deaths. The prevalence of genital HSV among people of child-bearing age (14–49 years) also differs by race/ethnicity, with non-Hispanic Black people having the highest seroprevalence of HSV type 2.27 For perinatal HIV and CS, inequities in incidence by race/ethnicity have been persistent and striking over time, with the highest rates among infants born to Black parents, followed by Hispanic/Latino parents, and lower rates among those born to White parents.12,16 The disproportionate burden of infant deaths related to HSV, HIV, and CS among Black birthing parents can be explained by racism, which leads to poverty, unemployment, residential segregation, and inequitable access to health care.28 Socioecological models highlight how the impacts of racism operate at multiple levels (individual, interpersonal, community, and societal), resulting in Black and African American women being at elevated risk for STIs and pregnancy-related complications.28 Our findings highlight the importance of focusing HSV-related prevention efforts on Black and African American women to reduce racial inequities in sexual and reproductive health.

This analysis is subject to the limitations of analyses that use vital records data. Death certificates have incomplete information on important clinical and laboratory characteristics, such as clinical syndrome and HSV viral type. In addition, death certificates did not capture information on race/ethnicity consistently across the study period, which precluded showing infant deaths by additional race/ethnicity categories, such as American Indian/Alaska Native, Asian, or Pacific Islander.

Misclassification may have also occurred at multiple points throughout the collection and management of vital records. First, cause of death information is dependent on complete and accurate identification and assignment of ICD codes on death certificates, a practice with a high error rate.29 Before making death records publicly available, NCHS staff edit the record axis (i.e., cause of death) fields for “rare causes and age/cause and sex/cause compatibility.”18 This cleaning process may impact the infections of interest in this investigation, which are infrequent causes of death overall, when compared with the 5 leading causes of infant death (e.g., congenital malformations, sudden infant death syndrome, and accidents), which in 2017 alone accounted for 12,462 infant deaths.19 Furthermore, we did not account for gestational age or other medical conditions that may have contributed to the deaths of infants with the infections of interest. Despite the potential for misclassification, the congruency between the HIV and CS trends we observed with national surveillance data supports the validity of the findings. In addition, a recent analysis in Florida showed that most provider- and laboratory-reported HSV-related deaths were identified in death certificates, highlighting the usefulness of this data source to assess HSV-related deaths in the absence of national reporting.10

Despite the markedly elevated and increasing burden of HSV-related deaths in the United States, neonatal herpes receives limited public health attention and resources30 when compared with perinatal HIV and CS, infections that the Centers for Disease Control and Prevention prioritize for prevention.15,16 Our findings underscore the need for elevating the importance of HSV infection in infants and pregnant people in the public health community at both the local and federal levels. At minimum, a standard case definition and investigation tool should be developed so that local jurisdictions have a consistent way to measure neonatal herpes case rates, which could lead to increased public health attention and advocacy.31 Multiple approaches to mitigating mortality are also needed and should include continued research toward an effective herpes vaccine,32 and implementation of rapid, point-of-care tests enabling timely identification of infants exposed to HSV at delivery.33 Infant mortality is a critical indicator of the health of a society, and it is incumbent on the United States to address neonatal herpes with the urgency and priority given to other congenitally and perinatally acquired infections,34 and to center efforts to reduce both mortality and morbidity related to HSV infection around reducing racial inequities.

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